S194: TECLISTAMAB (TEC) + NIROGACESTAT (NIRO) IN RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM): THE PHASE 1B MAJESTEC-2 STUDY
Authors: Fritz Offner, Olivier Decaux, Cyrille Hulin, Sébastien Anguille, Anne Sophie Michallet, Luciano Costa, Cyrille Touzeau, Kevin Boyd, Deeksha Vishwamitra, Yue Guo, Zhuolu Niu, Julie Larsen, Lingling Chen, Arnob Banerjee, Jenna Goldberg, Jeffrey Matous
Journal: HemaSphere (2023)

Background: Tec is the first BCMA-directed bispecific antibody approved for the treatment of triple-class exposed RRMM. Niro, a gamma secretase inhibitor, has been shown to potentiate BCMA-directed therapies in vitro and in clinical trials. Aims: We report initial results from one arm of the multicohort, open-label, phase 1b, MajesTEC-2 trial, which investigates tec with niro or other anticancer therapies in pts with MM. Methods: Pts were enrolled in the tec + niro cohort (age ≥18 years), had RRMM per International Myeloma Working Group (IMWG) criteria, had received ≥3 prior lines of therapy (LOT) or were double refractory to a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD) and triple exposed to a PI, an IMiD, and an anti-CD38 antibody, with progressive disease within 12 months (mo) of their last LOT. All pts provided informed consent. Three dose levels were evaluated: 1) tec 720 μg/kg weekly (QW) + concurrent niro (100 mg twice daily starting with first dose of tec; n=8); 2) tec 720 μg/kg QW + once daily (QD) delayed low-dose (LD) niro (100 mg QD starting after tec step-up dosing; n=7); and 3) tec 1500 μg/kg QW + QD delayed LD niro (n=13). Primary objectives for this cohort were to evaluate the safety and tolerability of tec + niro and identify optimal doses. Responses were investigator-assessed per IMWG criteria. Adverse events (AEs) were graded per CTCAE v5.0. Cytokine release syndrome (CRS) and ICANS were graded per ASTCT criteria. Results: As of Dec 16, 2022, 28 pts received tec + niro. Median (range) prior LOT was 4 (2–12). Median (range) duration of treatment (tx) was 9.4 mo (0.03–19.7) for tec and 4.7 mo (0.16–13.0) for niro. 67.9% of pts had International Staging System stage II/III disease; 20% had high-risk cytogenetics. Most frequent (>20%) tx-emergent AEs (TEAEs) for all doses were neutropenia (82.1%), CRS (75%), diarrhea (64.3%), injection-site erythema (53.6%), decreased appetite (50%), fatigue (42.9%), and anemia (35.1%). Of 8 pts who received tec 720 + concurrent niro, 2 dose-limiting toxicities (DLTs; 1 grade [gr] 3 GI bleed and gr 3 diarrhea; 1 gr 3 ICANS) were reported. In addition, 1 pt had gr 3 CRS and 1 had gr 3 confusional state. These AEs led to evaluation of delayed LD niro in the subsequent cohorts. In the tec 720 + QD delayed LD niro and tec 1500 + QD delayed LD niro groups, no DLTs or gr 3 CRS or neurologic AEs were reported. TEAEs led to delayed/skipped doses in 24 pts (85.7%). Six treatment-emergent deaths occurred: 3 with primary cause of death as AEs (septic shock, COVID-19, and cardiac arrest), 2 due to other causes, and 1 due to disease progression. The overall response rate was 71.4% (5/8 pts) for tec 720 + concurrent niro, 57.1% (4/7 pts) for tec 720 + QD delayed LD niro, and 92.3% (12/13 pts) for tec 1500 + QD delayed LD niro. Additional response data are shown in the table. Pharmacokinetics and pharmacodynamics were generally comparable to tec monotherapy. No anti-drug antibodies were detected. Summary/Conclusion: The combination of tec + niro yielded response rates of 57–92% across 3 dose levels assessed. This initial experience with tec + niro provides insights on the combination of BCMA-directed therapies with a gamma secretase inhibitor.Keywords: Phase I, Bispecific, Multiple myeloma, B-cell maturation antigen